Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

The toxicity to reproduction and developmental toxicity of the test substance TM 12-209 were investigated in a reproductive/developmental toxicity screening study according to OECD test guideline 421 in Wistar rat by dietary administration. The animals were exposed to the test substance via diet for 4 weeks before mating. After mating the males continued under the diet with test substance till necropsy on day 57. Females continued under the diet with test substance till necropsy on day 5 post partum. The dietary concentrations of test substance were 500, 3500 and 15000 ppm and each group had 12 animals per sex.

There were no unscheduled deaths. There were no clinical signs. No adverse effects were detected in body weight gain, food consumption, or water consumption for treated males throughout the treatment period or for treated females during maturation, gestation or lactation.

 

Males treated with 15000 and 3500 ppm showed an increase in absolute and relative liver and kidney weight.Males treated with 15000 and 3500 ppm showed a statistically significant (p<0.05) reduction in prostate weight both absolute and relative to terminal body weight. In the absence of a true dose related response or any associated histopathological correlates the intergroup differences were considered not to be of toxicological importance.

 

Treatment-related microscopic abnormalities include:

Liver:diffuse midzonal/centrilobular hypertrophy was noted at minimal degree in one male treated with 3500 ppm and at minimal or slight severity in eight males treated with 15000 ppm.

Kidneys:cortical hyaline droplets at minimal or slight severity was evident in nine control males, at minimal severity in nine males treated with 500 ppm, at minimal or slight degree in eleven males treated with 3500 ppm and at minimal to severe degree in all twelve males treated with 15000 ppm. Corticomedullary tubular basophilia was evident at minimal severity in two control males, in two males treated with 500 ppm, in four males treated with 3500 ppm and at minimal to moderate severity in eleven males treated with 15000 ppm. Granular casts at minimal to severe degree were also evident in eight males treated with 15000 ppm.

 

No treatment-related effects were detected in females therefore within the confines of this study,the NOEL for females was considered to be 15000 ppm. A NOEL for males has not been established due to the kidney findings in males from all treatment groups. The organ weight and microscopic liver changes (diffuse midzonal/centrilobular hypertrophy) detected in males treated with 15000 and 3500 ppm were considered to be an adaptive in nature and does not represent an adverse effect of treatment. Although the kidney findings in males treated with 15000 ppm, consisting of granular casts may be considered to represent an adverse effect of the test item, this finding was considered to be correlated to the finding of hyaline droplets, which is species and sex specific.Therefore, a No Observed Adverse Effect Level (NOAEL) can be established at 15000 ppm for males.

 

No treatment-related effects were detected in mating performance, fertility and gestation lengths. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 15000 ppm.


Short description of key information:
The developmental toxicity of Cosmofruit was experimentally determined in a reproduction/developmental toxicity screening study in rats via diet according to OECD TG 421 with 4 week of premating treatment. Males were terminated on Day 57, followed by the termination of females and offspring on Day 5 post partum. The NOEL for reproductive toxicity is considered as 15000 ppm the high dose tested. The NOEL for females systemic was considered to be 15000 ppm. A NOEL for males has not been established due to the kidney findings in males from all treatment groups. Although the kidney findings in males treated with 15000 ppm, consisting of granular casts may be considered to represent an adverse effect of the test item, this finding was considered to be correlated to the finding of hyaline droplets, which is species and sex specific. Therefore, a No Observed Adverse Effect Level (NOAEL) can be established at 15000 ppm for males.

Effects on developmental toxicity

Description of key information
The developmental toxicity of Cosmofruit was experimentally determined in a reproduction/developmental toxicity screening study in rats via diet according to OECD TG 421 with 4 week of premating treatment. Males were terminated on Day 57, followed by the termination of females and offspring on Day 5 post partum. The NOEL for developmental toxicity is considered as 15000 ppm the high dose tested. The NOEL for females systemic was considered to be 15000 ppm. A NOEL for males has not been established due to the kidney findings in males from all treatment groups.  Although the kidney findings in males treated with 15000 ppm, consisting of granular casts may be considered to represent an adverse effect of the test item, this finding was considered to be correlated to the same condition as hyaline droplets, which is species and sex specific. Therefore, a No Observed Adverse Effect Level (NOAEL) can be established at 15000 ppm for males.
Additional information

The toxicity to reproduction and developmental toxicity of the test substance TM 12-209 were investigated in a reproductive/developmental toxicity screening study according to OECD test guideline 421 in Wistar rat by dietary administration. The animals were exposed to the test substance via diet for 4 weeks before mating. After mating the males continued under the diet with test substance till necropsy on day 57. Females continued under the diet with test substance till necropsy on day 5 post partum. The dietary concentrations of test substance were 500, 3500 and 15000 ppm and each group had 12 animals per sex.

No adverse effects were detected in the number of corpora lutea, implantation sites or pre and post implantation losses. Of the litters born, litter size at birth and subsequently on Days 1 and 4post partumwere comparable to controls. Offspring body weight gain and litter weights on Days 1 and 4post partumwere comparable to control litters. Sex ratio and surface righting were also comparable to controls. The clinical signs and necropsy findings apparent for offspring on the study were typical for the age observed. Neither the incidence nor distribution of these observations indicated any adverse effect of maternal treatment on offspring development at 500, 3500 or 15000 ppm. Therefore the NOEL for developmental toxicity is considered as 15000 ppm the high dose tested.

Justification for classification or non-classification

Based on the absence of adverse effects on mating performance, fertility, gestation lengths, reproductive organs and of developmental toxicity in the Reproduction / Developmental Toxicity Screening Test in rats via diet (4-week premating period with total treatment of 8 weeks in males), classification of the test material for effects on fertility or developmental toxicity is not warranted in accordance with EU Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.